title: Materials characterization of the low temperature sensitive liposome (LTSL): effects of the lipid composition (lysolipid and DSPE-PEG2000) on the thermal transition and release of doxorubicin.
abstract: This paper describes how we have used material science, physical chemistry, and some luck, to design a new thermal-sensitive liposome (the low temperature sensitive liposome (LTSL)) that responds at clinically attainable hyperthermic temperatures releasing its drug in a matter of seconds as it passes through the microvasculature of a warmed tumor. The LTSL is composed of a judicial combination of three component lipids, each with a specific function and each affecting specific material properties, including a sharp thermal transition and a rapid on-set of membrane permeability to small ions, drugs and small dextran polymers. Experimentally, the paper describes how bilayer-concentration changes involving the lysolipid and the presence or absence of DSPE-PEG2000 affect both the lipid transition temperature and the drug release. While the inclusion of 4 mol% DSPE-PEG2000 raises the transition temperature peak (T(m)) by about 1 degrees C, the inclusion of 5.0, 9.7, 12.7 and 18.0 mol% MSPC slightly lowered this peak back to 41.7 degrees C, while not further broadening the peak breadth. As for drug release, in the absence of MSPC, the encapsulated doxorubicin-citrate is hardly released at all. Increasing the composition of MSPC in the lipid mixture (5.0, 7.4, 8.5 and 9.3 mol% MSPC) shows faster and faster initial doxorubicin release rates, with 8.5 and 9.3 mol% MSPC formulations giving 80% of encapsulated drug released in 4 and 3 min, respectively. The Thermodox formulation (9.7 mol% MSPC) gives 60% released in the first 20 s. The presence of PEG-lipid is found to be essential in order for the lysolipid-induced permeability to reach these very fast times. From drug and dextran release experiments, and estimates of the molecular and pore size, the conclusions are that: in order to induce lasting nanopores in lipid bilayers -10 nm diameter, they initially require the presence (from the solid phase structure) of grain boundary defects at the DPPC transition and the permeabilizing component(s) can either be a pore forming lysolipid/surfactant plus a PEG-lipid, or can be generated by a PEG-surfactant incorporated at -4-5 mol%. The final discussion is centered around the postulated defect structures that result in membrane leakage and the permeability of doxorubicin and H+ ions.
authors.affiliation: Duke University, Department of Mechanical Engineering and Materials Science, Box 90300 3391 CIEMAS, Durham, NC 27708, USA.
authors.forename: David
authors.initials: D
authors.lastname: Needham
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Park
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Wright
authors.forename: Jihong
authors.initials: J
authors.lastname: Tong
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics; D003911:Dextrans / Q000737:chemistry; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D010539:Permeability; D010714:Phosphatidylethanolamines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D013696:Temperature
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000903:Antibiotics, Antineoplastic; D003911:Dextrans; D008051:Lipid Bilayers; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D004317:Doxorubicin